Direct oral anticoagulants (DOACs) have become the foundation for prevention of thromboembolic complications in patients with nonvalvular (NV) atrial fibrillation (AF). Standard dosing, lack of required routine laboratory testing, and both minimal dietary and drug interactions compared with traditional vitamin K antagonists appeal to patients and physicians alike. Additionally, DOACs have demonstrated safety and efficacy for long-term oral anticoagulation in patients with NVAF. Current AF guidelines assign a Class I recommendation for warfarin, dabigatran, rivaroxaban, or apixaban as oral anticoagulant options in patients with NVAF, stating that choice should be individualized based on shared decision-making between the provider and patient.¹

With universal embracement of DOAC usage in NVAF, questions regarding periprocedural management are frequently encountered. Data are especially limited in patients undergoing electrophysiology (EP) and cardiac catheterization procedures, with various opinions not only on when to hold but also if to continue DOAC therapy through certain procedures. The following is a summary of current evidence on pre-procedural management of DOACs for EP and catheterization procedures.

Both thromboembolic and bleeding complications pose potentially devastating outcomes; thus, risks must be carefully balanced when considering management of pre-procedural anticoagulation. Procedural, as well as patient-related, bleed risks are equally crucial. In addition, thrombotic risk associated with discontinuation of anticoagulation must be considered. The DOACs vary substantially in pharmacokinetic properties, including dependence on renal excretion, so duration to hold anticoagulation may differ among the agents. The pharmacological properties of the four commercially available DOACs indicated for NVAF (dabigatran, rivaroxaban, apixaban, and edoxaban) are outlined in Table 1.^2-5 Although risks of major bleeding events with EP/catheterization procedures are relatively low, management of bleeding associated with DOACs can be challenging due to lack of available antidotes. In the event of a major bleeding complication, hemostatic agents must be used. Dabigatran has the only commercially available reversal agent, idarucizumab, which is a human monoclonal antibody fragment that neutralizes the anticoagulant effect of dabigatran by binding to the drug.⁶ Andexanet alfa is currently under review by the Food and Drug Administration as a potential antidote for factor Xa inhibitors and has shown rapid and substantial reversal of rivaroxaban and apixaban in patients with major bleeding.⁷ Another agent, aripazine (PER977, Ciraparantag), is under investigation for reversal of factor Xa inhibitors, direct thrombin inhibitors, and heparin.⁸ Given the multitude of factors that affect bleeding and thrombotic risk, decision-making surrounding DOACs prior to procedure is complex with considerable variability in clinical practice.

Table 1: Summary of DOACs in NVAF^2-5

	DABIGATRAN (Pradaxa®)	RIVAROXABAN (Xarelto®)	APIXABAN (Eliquis®)	EDOXABAN (Savaysa®)
Mechanism of Action	Direct thrombin inhibitor	Factor Xa inhibitor	Factor Xa inhibitor	Factor Xa inhibitor
Dosage in NVAF	150 mg BID creatinine clearance (CrCl) 15-30 ml/min: 75 mg bid	20 mg daily with evening meal CrCl 15-50 ml/min: 15 mg daily	5 mg bid 2.5 mg bid if ≥ 2 or more factors: age ≥ 80, SCr ≥ 1.5 mg/dl, weight ≤ 60 kg	60 mg daily in CrCl 50-95 ml/min CrCl 15-50 ml/min: 30 mg daily
Avoid Use/ Contra- indications	CrCl < 15 ml/min	CrCl < 15 ml/min Moderate-severe hepatic impairment Body weight ≥ 205 kg: do not use per manufacturer. Has only been studied up to 130 kg	CrCl < 15 ml/min Moderate-severe hepatic impairment	CrCl > 95 ml/min- increased risk of stroke CrCl < 15 ml/min Moderate-severe hepatic impairment
	Do not use in valvular heart disease, mechanical valves, or active pathological bleeding
Half-life	12-17 hours; prolonged in elderly patients and renal impairment Severe renal impairment: 28 hours	5-11 hours; 11-13 hours in elderly patients	12 hours	10-14 hours
Metabolism and Excretion	Esterase-catalyzed hydrolysis. 85% renal excretion unchanged	CYP3A4/5, CYP2J2, and hydrolysis metabolism. 66% renal excretion; 36% unchanged	Mainly CYP3A4; minor metabolism from CYP1A2, 2C8, 2C9, 2C19, and 2J2. 27% renal excretion; biliary and direct intestinal excretion	Minimal metabolism via hydrolysis, CYP3A4. Primarily eliminated unchanged. 50% renal excretion; biliary/intestinal excretion
Drug Interactions	Avoid use with P-gp inducers (i.e., carbamazepine, rifampin, ritonavir, St. John's wort, prazosin). P-gp inhibitors (i.e., dronedarone, ketoconazole, amiodarone) in CrCl 30-50 ml/min: reduce dose to 75 mg bid or avoid.	Avoid use with strong dual inhibitors of P-gp and CYP3A4 (i.e., clarithromycin, ketoconazole, ritonavir, itraconazole). CrCl 15-50 ml/min, avoid use with combined P-gp and moderate CYP3A4 inhibitors (i.e., amiodarone, diltiazem, dronedarone, azithromycin, verapamil, ranolazine, quinidine, erythromycin).	Strong dual inhibitors of P-gp and CYP3A4 (i.e., clarithromycin, ketoconazole, ritonavir, itraconazole): reduce dose to 2.5 mg bid. If on 2.5 mg bid, avoid concomitant use.	Do not use with rifampin.
	Increased risk of bleeding with other anticoagulants, antiplatelets, or chronic nonsteroidal anti-inflammatory drug use

Recently, the American College of Cardiology (ACC) released the 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation to provide guidance in this area.⁹ This publication addressed when to interrupt DOAC therapy, with pre-procedural hold times based on procedural bleed risk, type of agent, and renal function. Recommendations are summarized in Table 2. In deciding whether to interrupt DOAC therapy, the authors suggest first conducting an assessment of patient-related factors. Patient-related bleed risk is considered increased with any of the following: major bleed or intracranial hemorrhage within the past 3 months, platelet abnormality, including aspirin use, and history of bleed during previous bridging. If one or more factors are present, the ACC states that there are insufficient data on best practice and that DOAC therapy should be interrupted for at least as long as determined by CrCl (Table 2). If patient-related factors that increase bleed risk are not present, procedural bleed risk should be assessed and anticoagulation interrupted for a period of time based on type of DOAC and renal function (Table 2). The ACC classifies procedural bleeding risk into three categories: no clinically important risk; low risk; and uncertain, intermediate, or high risk. Common catheterization procedures were included (Table 3). Bleeding risk of coronary angiography and percutaneous coronary intervention (PCI) is based on vascular access site with preferred access via the radial artery due to lower risk of bleeding and vascular complications compared with the femoral approach. Risk of the common EP procedures, AF ablation, and implantable cardioverter-defibrillator (ICD) implantation were not defined by the ACC.

Table 2: Summary of ACC Recommendations for Pre-Procedural Management of DOACs in NVAF⁹

	LOW-RISK BLEEDING PROCEDURES	UNCERTAIN, INTERMEDIATE, OR HIGH-RISK BLEEDING PROCEDURES
Dabigatran (Pradaxa®)	HOLD based on CrCl*: CrCl 80 ml/min or higher: 24 hours (at least 2 doses) CrCl 50-79 ml/min: 36 hours (at least 3 doses) CrCl 30-49 ml/min: 48 hours (at least 4 doses) CrCl 15-29 ml/min: ≥ 72 hours Less than 15 ml/min: No data. Consider measuring dTT and/or withholding 96 hours or more.	HOLD based on CrCl*: CrCl 80 ml/min or higher: 48 hours (at least 4 doses) CrCl 50-79 ml/min: 72 hours (at least 6 doses) CrCl 30-49 ml/min: 96 hours (at least 8 doses) CrCl 15-29 ml/min: ≥ 120 hours Less than 15 ml/min: No data. Consider measuring dTT.
Rivaroxaban (Xarelto®)	HOLD based on CrCl*: CrCl 30 ml/min or higher: 24 hours CrCl 15-29 ml/min: 36 hours CrCl less than 15 ml/min: No data. Withhold for 48 hours or more.	HOLD based on CrCl*: CrCl 30 ml/min or higher: 48 hours CrCl less than 30 ml/min: No data. Withhold for 72 hours or more. Consider checking agent-specific anti-Xa level at 72 hours, if available.
Apixaban (Eliquis®)
Edoxaban (Savaysa®)

The American Heart Association (AHA) also recently released a Scientific Statement on management of patients on non-vitamin K oral anticoagulants in the acute care and periprocedural setting.¹⁰ Like the aforementioned ACC publication, the AHA authors discerned catheterization bleed risk based on vascular access but ranked bleed risk at a higher level for both catheterization and PCI (Table 3). Pre-procedural hold times for DOACs were based on their prescribing information. These recommendations differ from the ACC publication, which has more specific CrCl cutoffs and, in some cases, longer hold times. For instance, the ACC classifies PCI via the femoral artery as a moderate risk bleeding procedure, instructing to discontinue factor Xa inhibitors for 48 hours prior to procedure. This conflicts with the AHA, which categorizes catheterization via the femoral artery as a high-risk procedure but suggests a shorter hold time of at least 24 hours. Given the short half-lives of the DOACs, a hold time of 24 hours should be sufficient in patients with normal renal function. Of note, the AHA stipulates that bridging anticoagulation may be considered in patients in whom thromboembolic risk exceeds procedural bleeding risk, specifically those who have a history of systemic embolus in the last 6 weeks. The ACC authors state that parenteral bridging of DOACs is not indicated at any time due to their short half-lives.

Table 3: Classification of Bleeding Risk in Common EP/Catheterization Procedures (AHA and ACC)

Procedure	Peri-Procedural Bleeding Risk According to AHA	Peri-Procedural Bleeding Risk According to ACC
AF ablation	N/A	N/A
Supraventricular tachycardia ablation	Moderate	N/A
ICD implant	Moderate	N/A
Cardiac catheterization via femoral artery	High	Coronary angiography: Uncertain PCI: moderate
Cardiac catheterization via radial artery	Moderate	Low (coronary angiography and PCI)
Left atrial appendage occlusion (WATCHMAN [Boston Scientific; Marlborough, MA])	N/A	Moderate (intermediate)
Left atrial appendage occlusion (LARIAT procedure [SentreHEART, Inc; Palo Alto, CA])	N/A	High
Mitral valve repair, percutaneous (MitraClip [Abbott; Abbott Park, IL])	N/A	Moderate
Transaortic valve replacement	N/A	High
Right heart catheterization	N/A	Low

Management of pre-procedural anticoagulation is challenging in patients undergoing cardiac device insertion, particularly ICDs. Bleeding and pocket hematoma formation is a significant complication that can increase risk of infection and hospitalization.¹¹ Although uninterrupted warfarin has been associated with less bleeding, the optimal management of DOACs prior to ICD implantation is uncertain.¹² Small studies have observed no increased bleeding risk with uninterrupted dabigatran, but data have been insufficient to safely recommend continuing DOAC therapy through ICD implant procedures.^13,14 The results of BRUISE CONTROL-2 (A Randomized Controlled Trial of Continued Versus Interrupted Direct Oral Anti-Coagulant at the Time of Device Surgery) were recently presented at the 2017 AHA Annual Scientific Sessions.¹⁵ The study evaluated continued versus interrupted DOAC therapy with EP device procedure.¹⁶ Patients in the continued arm (n = 328) took their DOAC dose the morning prior to procedure, while those in the interrupted arm (n = 334) discontinued their DOAC 2 days prior to procedure. The primary outcome of clinically significant hematoma, as well as the secondary outcome of stroke, were the same for both groups (2.1 vs. 2.1%, p = 0.97 and 0.3 vs. 0.3%, p = 1.0, respectively). The trial was terminated early due to futility. The BRUISE-CONTROL 2 trial is the first large, randomized trial to show that the strategy of routine continuation of apixaban, rivaroxaban, or dabigatran is not superior to interrupted use in reduction of pocket hematomas. The study has yet to be published; nonetheless, the results may affect clinical practice and future guidance documents. The most recent AHA Scientific Statement offers some guidance on management of DOACs in the pre-procedural period, listing ICD implantation as a moderate bleed risk procedure with a suggested hold time of 24 hours for factor Xa inhibitors. For dabigatran, they recommend hold time based on renal function as indicated for ACC-defined low-risk bleeding procedures (Table 2).

Similar to cardiac device insertion, periprocedural anticoagulation for AF ablation has been an area of intense debate since the procedure was first described by Haisseguerre and others in the late 1980s and continues in the era of DOAC therapy.^17-19 AF ablation adds greater complexity to procedural risk mitigation because patients are at an elevated risk of cerebral thromboembolism and, in most cases, require anticoagulation for at least 3 weeks prior to procedure. Furthermore, it has been estimated that the periprocedural risk of cardiac tamponade is 1.5%.²⁰ The use of uninterrupted warfarin in the setting of AF ablation is a widely accepted strategy due to ample evidence indicating decreased thromboembolic and bleeding events. Several observational studies have demonstrated safety of uninterrupted DOAC therapy in the setting of AF ablation.^20-22 Of late, new AF ablation guidelines were published (2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation), providing a Class I recommendation for performing AF ablation with uninterrupted dabigatran or rivaroxaban and a Class 2A recommendation for the other DOACs.²⁰ These recommendations were largely based on the results of the RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy) study, which randomized 704 patients with AF undergoing catheter ablation to either uninterrupted dabigatran versus uninterrupted warfarin.²³ The patients in the dabigatran group took their morning dose as scheduled on the day of procedure. The primary endpoint of the incidence of major bleeding events up to 8 weeks post-ablation was significantly lower in the dabigatran arm than the warfarin (1.6 vs. 6.9% respectively, p < 0.001). One patient in the warfarin group experienced a thromboembolic event compared with none in the dabigatran group. The guidelines were also based on another smaller scale, head-to-head study comparing uninterrupted rivaroxaban versus uninterrupted warfarin in 248 patients undergoing catheter ablation.²⁴ The incidence of major bleeding was low, with only one event in the warfarin group. Thromboembolic events were also few, with one ischemic stroke and one vascular death in the warfarin arm.

With the advent of DOACs and simplified anticoagulation therapy comes a complexity of pre-procedural management in balancing both bleeding and thromboembolic risks. Specifically, limited evidence exists on the safety and efficacy of DOAC use in patients with NVAF undergoing EP/catheterization procedures. Newly released guidelines recommend performing AF ablation in the setting of uninterrupted DOAC therapy, but management in other EP/catheterization procedures has been unclear. Both the AHA and ACC have recently published separate documents providing guidance for clinicians who manage patients on DOACs in the peri-procedural setting. However, there are inconsistencies between the two groups in recommended hold times of DOACs and classification of procedural bleed risk. This demonstrates a clear need for standard definitions of procedural risk, hold times of DOACs, and "uninterrupted" versus "interrupted" therapy. New evidence, such as that from the BRUISE-CONTROL 2 trial, may help steer future guidelines. In the interim, institution-specific recommendations and protocols should be developed for consistent DOAC management among local providers.

References

1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-76.
2. Pradaxa Prescribing Information (Boehringer Ingelheim Pharmaceuticals, Inc website). 2017. Available at: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. Accessed 09/02/2017.
3. Xarelto Prescribing Information (Janssen Pharmaceuticals, Inc. website). 2011. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf. Accessed 09/02/2017.
4. Eliquis Prescribing Information (Bristol-Myers Squibb Company, Pfizer Inc. website). 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf. Accessed 08/30/2017.
5. Savaysa Prescribing Information (Daiichi Sankyo Inc. website). 2015. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. Accessed 08/30/2017.
6. Praxbind Prescribing Information (Boehringer Ingelheim Pharmaceuticals, Inc. website). 2015. Available at: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Praxbind/Praxbind.pdf. Accessed 09/02/2017.
7. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 2016;375:1131-41.
8. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371:2141-2.
9. Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017;69:871-98.
10. Raval AN, Cigarroa JE, Chung MK, et al. Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association. Circulation 2017;135:e604-e633.
11. Essebag V, Verma A, Healey JS, et al. Clinically Significant Pocket Hematoma Increases Long-Term Risk of Device Infection: BRUISE CONTROL INFECTION Study. J Am Coll Cardiol 2016;67:1300-8.
12. Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013;368:2084-93
13. Rowley CP, Bernard ML, Brabham WW, et al. Safety of continuous anticoagulation with dabigatran during implantation of cardiac rhythm devices. Am J Cardiol 2013;111:1165-8.
14. Jennings JM, Robichaux R, McElderry HT, et al. Cardiovascular implantable electronic device implantation with uninterrupted dabigatran: comparison to uninterrupted warfarin. J Cardiovasc Electrophysiol 2013;24:1125-9.
15. A Randomized Controlled Trial of Continued Versus Interrupted Direct Oral Anti-Coagulant at the Time of Device Surgery - BRUISE CONTROL-2. Presented by Dr. David H. Birnie at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 12, 2017.
16. Essebag V, Healey JS, Ayala-Parades F, et al. Strategy of continued vs interrupted novel oral anticoagulant at time of device surgery in patients with moderate to high risk of arterial thromboembolic events: The BRUISE CONTROL-2 trial. Am Heart J 2016;173:102-7.
17. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006;114:759-65.
18. Wazni OM, Rossillo A, Marrouche NF, et al. Embolic events and char formation during pulmonary vein isolation in patients with atrial fibrillation: impact of different anticoagulation regimens and importance of intracardiac echo imaging. J Cardiovasc Electrophysiol 2005;16:576-81
19. Asirvatham SJ. Ablation for atrial fibrillation: can we decrease thromboembolism without increasing the risk for bleeding? Circulation 2007;116:2517-9.
20. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017;14:e275-e444.
21. Lakkireddy D, Reddy YM, Di Biase LD, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014;63:982-8.
22. Wu S, Yang YM, Zhu J, et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants Compared With Uninterrupted Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation. Am J Cardiol 2016;117:926-34.
23. Calkins, H, Willems S, Gerstenfeld EP, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med 2017;376:1627-36.
24. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015;36:1805-11.

Keywords: Amiodarone, Anticoagulants, Antidotes, Antithrombins, Aspirin, Atrial Appendage, Atrial Fibrillation, Azithromycin, Blood Platelets, Body Weight, Carbamazepine, Cardiac Catheterization, Cardiac Tamponade, Catheter Ablation, Clarithromycin, Coronary Angiography, Creatinine, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System, Defibrillators, Implantable, Diltiazem, Drug Combinations, Drug Interactions, Electrophysiology, Embolism, Esterases, Factor V, Factor Xa, Factor Xa Inhibitors, Femoral Artery, Glomerular Filtration Rate, Half-Life, Heart Valve Diseases, Hematoma, Hemostatics, Heparin, Hospitalization, Hydrolysis, Immunoglobulin Fragments, Intracranial Hemorrhages, Itraconazole, Ketoconazole, Medical Futility, Mitral Valve, Percutaneous Coronary Intervention, Prazosin, Pulmonary Veins, Pyrazoles, Pyridines, Pyridones, Quinidine, Radial Artery, Rifampin, Ritonavir, Stroke, Tachycardia, Supraventricular, Thiazoles, Thrombin, Thromboembolism, Verapamil, Vitamin K, Warfarin, Arrhythmias, Cardiac

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